AORTA, BRAIN AND KIDNEY STRUCTURE AND FUNCTION IN THE AGES-REYKJAVIK STUDY

描述（由申请人提供）：主动脉僵硬度在60岁后急剧增加，并与心脏病、中风、认知障碍和肾脏疾病的风险增加有关。尽管已经确定了导致主动脉僵硬异常的几个危险因素，但从危险因素到主动脉功能障碍、过压性搏动以及脑和肾的下游损伤的因果通路的基本机制仍不完全清楚。主动脉硬化和血压过速与微血管重构、肥厚和反应性受损有关，这可能导致终末器官损伤。我们建议在雷克雅未克年龄、基因/环境易感性研究（AGES-Reykjavik）中对4000名参与者的大脑进行动脉血压计和详细的磁共振成像（MRI），对600名参与者的主动脉和肾脏进行MRI。我们对这个提议的假设有三点：1)主动脉弓近端管壁硬化和主动脉直径与血流不匹配是老年人压力性脉搏过速的主要原因；2)由此产生的脉压升高对小血管结构和功能有不利影响，表现为脑（脑血管输入阻抗）和肾（肾血管输入阻抗）的异常压流关系，因为这些高流量器官对脉动损伤非常敏感；3)由此产生的脑血管和肾功能异常与脑和肾结构（MRI）和功能（认知）异常有关检查，肾小球滤过率，蛋白尿)。我们的具体目标是：1)将中央和外周脉压与主动脉结构和功能的详细测量联系起来。我们将利用MRI检查主动脉直径、壁厚、刚度和沿主动脉全长关键水平的血流，以综合评估主动脉功能各组成部分对脉压升高发病机制的空间异质性贡献。2)探讨主动脉功能（动脉血压计）、脑血管输入阻抗与脑结构（定量MRI）和功能（标准化认知测试）的关系。在基于社区的AGES-Reykjavik研究中，我们将使用动脉血压计和脑总血流量，对4000名参与者进行脑血管输入阻抗的全面无创评估，并将脑血管异常与脑结构和认知功能联系起来。3)将主动脉和肾血管功能指标与肾脏结构和功能联系起来。这项研究将为心血管疾病危险因素、脉压升高和随着年龄增长的脑和肾功能下降之间的关系提供关键的机制见解。60岁以后主动脉僵硬异常和血压搏动增加非常普遍，并增加了患心脏病、中风、痴呆和肾病的风险。主动脉硬化的高患病率、不良后果的高风险和人口老龄化的结合预示着由主动脉功能异常引起的疾病负担的急剧增加，除非采取措施预防或逆转老年人的主动脉硬化。本研究将确定导致主动脉硬化的因素，并确定异常硬化对大脑和肾脏结构和功能的不利影响。

DESCRIPTION (provided by applicant): Aortic stiffness increases dramatically after 60 years of age and is associated with increased risk for heart disease, stroke, cognitive impairment and kidney disease. Although several risk factors for abnormal aortic stiffness have been identified, basic mechanisms in the causal pathway from risk factor to aortic dysfunction to excessive pressure pulsatility and downstream damage in the brain and kidney remain incompletely understood. Aortic stiffening and excessive blood pressure pulsatility are associated with microvascular remodeling, hypertrophy and impaired reactivity, which may contribute to end-organ damage. We propose to perform arterial tonometry and detailed magnetic resonance imaging (MRI) of the brain in 4000 participants and MRI of the aorta and kidneys in 600 participants in the Age, Gene/Environment Susceptibility- Reykjavik study (AGES-Reykjavik). Our hypotheses for this proposal are 3 fold: 1) that wall stiffening in the proximal aortic arch and mismatch between aortic diameter and flow are major sources of excessive pressure pulsatility in older people, 2) that the consequent increase in pulse pressure has detrimental effects on small vessel structure and function that manifest as abnormal pressure-flow relations in the brain (cerebrovascular input impedance) and kidneys (renovascular input impedance) because these high-flow organs are highly susceptible to pulsatile damage and 3) that the resulting abnormalities in cerebrovascular and renovascular function are associated with abnormal brain and kidney structure (MRI) and function (cognitive testing, glomerular filtration rate, albuminuria). Our specific aims are: 1) To relate central and peripheral pulse pressure to detailed measures of aortic structure and function. Using MRI, we will examine aortic diameter, wall thickness, stiffness and flow at key levels along the full length of the aorta in order to evaluate comprehensively the spatially heterogeneous contribution of each component of aortic function to the pathogenesis of increased pulse pressure. 2) To examine relations between aortic function (arterial tonometry), cerebrovascular input impedance and brain structure (quantitative MRI) and function (standardized cognitive testing). Using arterial tonometry and total brain blood flow, we will perform a comprehensive noninvasive assessment of cerebrovascular input impedance and will relate cerebrovascular abnormalities to brain structure and cognitive function in 4000 participants in the community-based AGES-Reykjavik study. 3) To relate measures of aortic and renovascular function to kidney structure and function. This study will provide critical mechanistic insights into the relations between cardiovascular disease risk factors, increased pulse pressure and declining brain and kidney function with advancing age. PUBLIC HEALTH RELEVANCE: Project Narrative Abnormal aortic stiffness and increased blood pressure pulsatility are highly prevalent after 60 years of age and convey increased risk of heart disease, stroke, dementia and kidney disease. The combination of high prevalence of aortic stiffness, high risk for an adverse outcome and aging of the population portends a dramatic increase in the burden of disease attributable to abnormal aortic function unless steps are taken to prevent or reverse aortic stiffening in older people. This study will identify factors that contribute to aortic stiffening and will define the adverse effects of abnormal stiffness on structure and function of brain and kidneys.